Influenza A viruses are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. In 2009, a novel pandemic emerged and its impact is not yet fully understood. Understanding the molecular basis for the formation of pandemic influenza strains is critical. The 1957 and 1968 pandemics were human-avian reassortant viruses in which two or three influenza gene segments from the then circulating human influenza viruses were replaced with genes from an avian source. The 2009 pandemic virus arose via reassortment between two swine-adapted influenza viruses. Sequence and phylogenetic analysis of the 1918 pandemic virus suggested that it was derived from an avian-like virus possibly via an intermediate host in the decade before the pandemic. The 1918 pandemic virus caused several epidemiologically distinct waves. The so-called first wave, in the summer months of 1918, may have represented an early form of the more virulent second wave. To understand how this pandemic virus emerged and to model its virulence, it is important to place this virus in the context of human influenza viruses circulating before 1918 and to follow the early evolution of human H1N1 viruses after 1918. Because human influenza isolates are not available earlier than 1933, the only way to characterize these viruses is by identification of influenza RNA fragments preserved in formalin-fixed, paraffin-embedded autopsy tissues. Re-evaluation of the histopathology in 1918 influenza cases: We performed a detailed histopathologic review of 1918 pandemic influenza autopsy cases from 68 influenza and pneumonia cases of patients dying between May and October 1918, a period which includes approximately 4 months before the 1918 pandemic was recognized, and two months (September-October, 1918) during which it appeared and peaked. The cases were from the archives of the Armed Forces Institute of Pathology. The lung tissues of 37 of these cases were positive for influenza viral antigens or viral RNA, including 4 from the pre-pandemic period (May-August). The pre-pandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases had histological evidence of bacterial pneumonia, and 94% showed abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases suggested a trend from a more avian-like viral receptor specificity with G222 in pre-pandemic cases to a more human-like specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the respiratory tree, however, was not apparently different between pre-pandemic and pandemic peak cases, or between infections with viruses bearing different receptor binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 months in the U.S. before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implications for understanding the origins and evolution of pandemic influenza viruses. The distribution of viral antigen was similar to that observed from autopsy studies previously performed on fatal 2009 pandemic influenza autopsy cases. Prominent staining was observed in the respiratory epithelium of the tracheobronchial tree, but with clear evidence of viral antigen in alveolar epithelial cells and macrophages. One 1918 pneumonia case also showed abundant erythrocyte sickling. DNA sequence analysis of the hemoglobin beta gene identified the mutation associated with sickle cell anemia. Influenza infections, as seasonal influenza, pandemic influenza, and animal epizootics of influenza have been reported in the medical literature for hundreds of years. In a series of analyses of historical data, information on past pandemics as early as 1510 were reviewed. Despite the current notion that pandemic influenza is a distinct phenomenon obeying such constant (if incompletely understood) rules such as dramatic genetic change, cyclicity, "wave" patterning, virus replacement, and predictable epidemic behavior, much evidence suggests the opposite. Pandemics arise as a result of various genetic mechanisms, have no apparent predictable patterns of mortality among different age groups, and vary greatly in how and when they arise and recur. Some are followed by new pandemics, whereas others fade gradually or abruptly into long-term endemicity. Human influenza pandemics have been caused by viruses that evolved singly or in co-circulation with other pandemic virus descendants and often have involved significant transmission between, or establishment of, viral reservoirs within other animal hosts. In recent decades, pandemic influenza has continued to produce numerous unanticipated events that expose fundamental gaps in scientific knowledge. Influenza pandemics appear to be not a single phenomenon but a heterogeneous collection of viral evolutionary events whose similarities are overshadowed by important differences, the determinants of which remain poorly understood. These uncertainties make it difficult to predict influenza pandemics and, therefore, to adequately plan to prevent them.